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Diet-induced models of chronic kidney disease (CKD) offer several advantages, including clinical relevance and animal welfare, compared with surgical models. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. An increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction, and eventually CKD. Dahl-Salt-Sensitive (SS) rats are a common strain used to study hypertensive renal disease; however, the characterization of other diet-induced models on this background would allow for comparative studies of CKD within the same strain. In the present study, we hypothesized that SS rats on a low-salt, oxalate rich diet would have increased renal injury and serve as novel, clinically relevant and reproducible CKD rat models. Ten-week-old male SS rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks.Real-time PCR demonstrated an increased expression of inflammatory marker interleukin-6 (IL-6) (p < 0.0001) and fibrotic marker Timp-1 metalloproteinase (p < 0.0001) in the renal cortex of SS-OX rat kidneys compared with SS-NC. The immunohistochemistry of kidney tissue demonstrated an increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats (p < 0.001). In addition, SS-OX rats displayed increased 24 h urinary protein excretion (UPE) (p < 0.01) as well as significant elevations in plasma Cystatin C (p < 0.01). Furthermore, the oxalate diet induced hypertension (p < 0.05). A renin–angiotensin–aldosterone system (RAAS) profiling (via liquid chromatography–mass spectrometry; LC–MS) in the SS-OX plasma showed significant (p < 0.05) increases in multiple RAAS metabolites including angiotensin (1–5), angiotensin (1–7), and aldosterone. The oxalate diet induces significant renal inflammation, fibrosis, and renal dysfunction as well as RAAS activation and hypertension in SS rats compared with a normal chow diet. This study introduces a novel diet-induced model to study hypertension and CKD that is more clinically translatable and reproducible than the currently available models.

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Hypertension is an important clinical symptom of metabolic syndrome (MetS). Rats selectively bred for low intrinsic aerobic capacity (LCR) are animal models for MetS, and present with increased blood pressure and vascular dysfunction. In contrast, rats selected for high intrinsic aerobic capacity (HCR) display reduced vascular inflammation and no metabolic abnormalities. Two important enzymes for vascular inflammation and the resolution of inflammation are cyclooxygenase (COX) and lipoxygenase (LOX), respectively; however, it is unknown whether COX and LOX play a role in the vascular function of LCR and HCR. We hypothesized that mesenteric resistance arteries (MRA) from untrained LCR present increased COX activity, while arteries from HCR show decreased COX and increased LOX activity. Female (18-38 weeks old) LCR, HCR, and high response trained (HRT) rats, control, were used. HRT rats present higher intrinsic aerobic capacity than LCR, but lower than HCR. MRA were mounted onto a wire myograph. One-way ANOVA: p<0.05: *vs. control (HRT); # vs. HCR; & vs. absence of indomethacin (INDO), a COX inhibitor. LCR rats showed increased periovarian fat pad [HRT: 0.95±0.1 (n=7) vs. LCR: 1.80±0.1* # (n=7) vs. HCR: 1.18±0.1 (n=7) (g)]. No significant differences were observed in the KCl (120 mM), acetylcholine, and sodium-nitroprusside-induced responses. However, LCR presented a decrease in phenylephrine (PE)-induced contraction [PE: E max %: HRT: 103±3 (n=8); LCR: 74±9* # (n=11); HCR: 112±5 (n=9)]. Inhibiting COX [INDO, 10 μM] decreased contraction in HRT arteries, but had little effect on HCR arteries. Contrarily, INDO abolished contraction in MRA from LCR [PE+INDO: E max %: HRT: 31±18 & (n=7); LCR: 2±0.9 & (n=8); HCR: 77±9 (n=8)]. Lipoxin (LXA4), a LOX-derived mediator for resolution of inflammation, induced contraction in MRA from HCR, but relaxation in LCR and HRT arteries [LXA4: E max %: HRT: -69±19 (n=4); LCR: -18±9 (n=3); HCR: 11±5 (n=4)*]. Thus, HCR are unresponsive to COX inhibition, suggesting a change from a normal inflammatory state to a higher resolution state. LCR display low-grade chronic inflammation via increased COX activity. These data reveal novel, inherited mechanisms for vascular physiology in high vs. low intrinsic aerobic capacity.